Since the beginning of medical history, atherosclerosis has been described as an important disease. However, only in the twentieth century was it discovered that myocardial infarction is always associated with coronary atherosclerosis and thrombosis. Epidemiologic studies carried out in the seventies have shown that about fifty percent of all mortalities in the Western industrialized countries are caused by cardiovascular disease.
The most important factors in the development of atherosclerosis are known. The importance of elevated cholesterol and triglyceride concentrations was discovered early. Cholesterol and triglycerides are transported in the form of so-called lipoproteins, the cholesterol-rich low-density (LDL) and triglyceride-rich very low-density (VLDL) fractions of which are considered as atherogenic if their concentrations in the blood are increased.
However, only recently was it discovered that in addition to their amount, the "quality" of LDL is also decisive. Thus, in animal experiments it could be shown that equally high concentrations of LDL cholesterol were more or less atherogenic depending upon the properties of the drug applied to redued the elevated LDL cholesterol level. The cause of this finding could also be shown by the authors, namely, a drug which was also able to reduce LDL oxidation was most effective in counteracting atherosclerosis. (Carew et al., Proc. Nat. Acad. Sci. USA 84, 7725-7729 (November 1987. )) This experiment impressively demonstrates the importance of LDL "quality". In the body, LDL and VLDL are subject to continual oxidation which is physiologically balanced by natural so-called antioxidants such as tocopherol or ascorbic acid. However, in the case of increased LDL (cholesterol) and VLDL (triglyceride) values, this homeostasis is disturbed and shifted in favor of an increasing tendency towards oxidation.
Therefore, the risk of development and manifestation of atherosclerosis is increased by two factors:
elevated concentration of so-called atherogenic lipoproteins (LDL, VLDL) and PA1 their content of oxidation products (e.g., oxidized lipids). PA1 nicotinic acid or a suitable derivative thereof as the lipid-lowering principle. PA1 an antioxidant as the antiatherosclerosis principle. PA1 effective in reducing lipids without induction of excessively high levels of nicotinic acid; PA1 effective in counteracting lipid and lipoprotein oxidation; PA1 effective in reducing endothelial damage due to oxidized LDL; and PA1 effective in reducing the proliferation of smooth muscle cells in the vascular wall.
Causal treatment must, therefore, influence both factors.
Apart from the humoral factors, namely the lipoproteins, the cellular constituents of the vascular wall play an important role in atherogenesis. Thus, in the case of mechanical or chemical damage of the internal vascular coating, the endothelium, a proliferation impulse is generated to stimulate the underlying layer of smooth muscle cells. This process is particularly impressive after endothelial damage as a result of angioplasty. Within a relatively short time the induced proliferate can block the vessel to such an extent that an infarction may occur. In addition to mechanical endothelial damage, noxae such as oxidized LDL play also an important part.
Therefore, in addition to the two possibilities mentioned above, effective atherosclerosis intervention must be aimed at protecting the endothelium and reducing excessive proliferation of smooth muscle cells.
Compounds fulfilling all the above-mentioned requirements should comprise two pharmacologically differently-acting moieties, at least:
Nicotinic acid is the drug of choice as it acts not only on lipids but has been shown to have antiatherosclerolic properties of its own.
Yet, for medication purposes, one must circumvent the known side effects of nicotinic acid, e.g., flush due to a too rapid increase of nicotinic acid concentration in the blood. In fact, it has been found that rapid increases and high levels of nicotinic acid are not necessary to achieve the lipid-lowering effect. Thus, low nicotinic acid concentrations and sufficient reduction of lipids should be the main prerequisites of valuable compounds of the aforementioned type.
DE 2716125 discloses, as a preferred compound, a BHT (butylated hydroxy toluene) ether derivative (herein named Mrz 3/156) of the formula: ##STR2##
When tested for the required properties, excessively high levels of nicotinic acid (cf. Table 1) were observed, thereby demonstrating that this compound does not fulfill the stated requirements.
Extensive and painstaking synthetic and pharmacological efforts have revealed that there are several structural prerequisites necessary to meet all the criteria.
It was concluded that only compounds of the below-mentioned general formula are of interest.
It could be shown that the compounds according to the invention are